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Journal of Lipid Research, Vol. 49, 1176-1186, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Sphingolipids. Nuclear sphingolipids: metabolism and signaling^*

Robert W. Ledeen¹ and Gusheng Wu

Department of Neurology & Neurosciences, New Jersey Medical School, The University of Medicine and Dentistry of New Jersey, Newark, NJ 07103

^* This study was supported by National Institutes of Health grant 2RO1 NS033912.

Published, JLR Papers in Press, March 9, 2008.

¹ To whom correspondence should be addressed. e-mail: ledeenro{at}umdnj.edu

Sphingolipids are most prominently expressed in the plasma membrane, but recent studies have pointed to important signaling and regulatory roles in the nucleus. The most abundant nuclear sphingolipid is sphingomyelin (SM), which occurs in the nuclear envelope (NE) as well as intranuclear sites. The major metabolic product of SM is ceramide, which is generated by nuclear sphingomyelinase and triggers apoptosis and other metabolic changes. Ceramide is further hydrolyzed to free fatty acid and sphingosine, the latter undergoing conversion to sphingosine phosphate by action of a specific nuclear kinase. Gangliosides are another type of sphingolipid found in the nucleus, members of the a-series of gangliotetraose gangliosides (GM1, GD1a) occurring in the NE and endonuclear compartments. GM1 in the inner membrane of the NE is tightly associated with a Na⁺/Ca²⁺ exchanger whose activity it potentiates, thereby contributing to regulation of Ca²⁺ homeostasis in the nucleus. This was shown to exert a cytoprotective role as absence or inactivation of this nuclear complex rendered cells vulnerable to apoptosis. This was demonstrated in the greatly enhanced kainite-induced seizure activity in knockout mice lacking gangliotetraose gangliosides. The pathology included apoptotic destruction of neurons in the CA3 region of the hippocampus. Ca²⁺ homeostasis was restored in these animals with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na⁺/Ca²⁺ exchanger. Some evidence suggests the presence of uncharged glycosphingolipids in the nucleus.

Supplementary key words sphingolipid • sphingomyelin • sphingomyelinase • ceramide • sphingosine phosphate • gangliosides • nuclear calcium • ganglioside GM1

Abbreviations: CER, ceramide; CGN, cerebellar granule neurons; Ctx B, cholera toxin B subunit; DAG, diacylglycerol; ER, endoplasmic reticulum; Gb₃, globotraosylceramide; HRP, horseradish peroxidase; NCX, sodium calcium exchanger; NE, nuclear envelope; S-1-P, sphingosine phosphate; SM, sphingomyelin; SMase, sphingomyelinase

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